Canonical androgen response element motifs are tumor suppressive regulatory elements in the prostate.

The androgen receptor (AR) is central in prostate tissue identity and differentiation, and controls normal growth-suppressive, prostate-specific gene expression. It also drives prostate tumorigenesis when hijacked for oncogenic transcription. The execution of growth-suppressive AR transcriptional programs in prostate cancer (PCa) and the potential for reactivation remain unclear.

Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase.

We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound .

Trends in Active Surveillance for Men With Intermediate-Risk Prostate Cancer.

Importance: Initial management of intermediate-risk prostate cancer is evolving, with no clear recommendation for treatment. Data on utilization of active surveillance for patients with newly diagnosed intermediate-risk prostate cancer may help clarify emerging trends.

Objective: To further characterize US national trends of initial management of intermediate-risk prostate cancer.

Radiation therapy and IRreversible electroporation for intermediate risk prostate cancer (RTIRE).

Introduction: Radiation Therapy and IRreversible Electroporation for Intermediate Risk Prostate Cancer (RTIRE) is a phase II clinical trial testing combination of radiation therapy and irreversible electroporation for intermediate risk prostate cancer BACKGROUND: PCa is the most common non-cutaneous cancer in men and the second leading cause of cancer death in men. PCa treatment is associated with long term side effects including urinary, sexual, and bowel dysfunction. Management of PCa is based on risk stratification to prevent its overtreatment and associated treatment-related toxicity.

USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity.

Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here, we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer (PCa).

Transcriptomic Profiling of Primary Prostate Cancers and Nonlocalized Disease on Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.

Purpose: To characterize the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-based metastatic spread.

Materials And Methods: We identified patients from four institutions who underwent PSMA PET/CT scans pretreatment for primary staging or postradical prostatectomy (RP) for suspected recurrence and had Decipher transcriptomic data available from biopsy or RP specimens. PSMA PET/CT-based patterns of spread were classified as localized (miT + N0M0) or nonlocalized (miN1M0 or miM1a-c).

Canonical AREs are tumor suppressive regulatory elements in the prostate.

The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression . It is also a key driver of prostate tumorigenesis, becoming "hijacked" to drive oncogenic transcription . However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear.

Distinct mesenchymal cell states mediate prostate cancer progression.

In the complex tumor microenvironment (TME), mesenchymal cells are key players, yet their specific roles in prostate cancer (PCa) progression remain to be fully deciphered. This study employs single-cell RNA sequencing to delineate molecular changes in tumor stroma that influence PCa progression and metastasis. Analyzing mesenchymal cells from four genetically engineered mouse models (GEMMs) and correlating these findings with human tumors, we identify eight stromal cell populations with distinct transcriptional identities consistent across both species.

Plasma metabolomics profiling of 580 patients from an Early Detection Research Network prostate cancer cohort.

Prostate cancer is the second most common cancer in men and affects 1 in 9 men in the United States. Early screening for prostate cancer often involves monitoring levels of prostate-specific antigen (PSA) and performing digital rectal exams. However, a prostate biopsy is always required for definitive cancer diagnosis.

Differential Use of Radiotherapy Fractionation Regimens in Prostate Cancer.

Importance: Technical advances in treatment of prostate cancer and a better understanding of prostate cancer biology have allowed for hypofractionated treatment courses using a higher dose per fraction. Use of ultrahypofractionated stereotactic body radiotherapy (SBRT) has also been characterized.

Objective: To characterize US national trends of different RT fractionation schemes across risk groups of prostate cancer.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

Background: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens.

SPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor-Induced Growth Suppression.

Purpose: Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP substrate-binding cleft are found in up to 15% of prostate cancers. While mutations in SPOP predict for benefit from androgen receptor signaling inhibition (ARSi) therapy, outcomes for patients with SPOP-mutant (SPOPmut) prostate cancer are heterogeneous and targeted treatments for SPOPmut castrate-resistant prostate cancer (CRPC) are lacking.

Prostate cancer genetic alterations in Hispanic men.

Background: Differences in DNA alterations in prostate cancer among White, Black, and Asian men have been widely described. This is the first description of the frequency of DNA alterations in primary and metastatic prostate cancer samples of self-reported Hispanic men.

Methods: We utilized targeted next-generation sequencing tumor genomic profiles from prostate cancer tissues that underwent clinical sequencing at academic centers (GENIE 11th).

Impact of Magnetic Resonance Imaging Targeting on Pathologic Upgrading and Downgrading at Prostatectomy: A Systematic Review and Meta-analysis.

Context: The evidence supporting multiparametric magnetic resonance imaging (MRI) targeting for biopsy is nearly exclusively based on biopsy pathologic outcomes. This is problematic, as targeting likely allows preferential identification of small high-grade areas of questionable oncologic significance, raising the likelihood of overdiagnosis and overtreatment.

Objective: To estimate the impact of MRI-targeted, systematic, and combined biopsies on radical prostatectomy (RP) grade group concordance.

Distinct mesenchymal cell states mediate prostate cancer progression.

Alterations in tumor stroma influence prostate cancer progression and metastatic potential. However, the molecular underpinnings of this stromal-epithelial crosstalk are largely unknown. Here, we compare mesenchymal cells from four genetically engineered mouse models (GEMMs) of prostate cancer representing different stages of the disease to their wild-type (WT) counterparts by single-cell RNA sequencing (scRNA-seq) and, ultimately, to human tumors with comparable genotypes.

SMAD3 promotes expression and activity of the androgen receptor in prostate cancer.

Overexpression of androgen receptor (AR) is the primary cause of castration-resistant prostate cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNA-seq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin.

Race and prostate cancer: genomic landscape.

In the past 20 years, new insights into the genomic pathogenesis of prostate cancer have been provided. Large-scale integrative genomics approaches enabled researchers to characterize the genetic and epigenetic landscape of prostate cancer and to define different molecular subclasses based on the combination of genetic alterations, gene expression patterns and methylation profiles. Several molecular drivers of prostate cancer have been identified, some of which are different in men of different races.

Impact of Left-Digit Age Bias in the Treatment of Localized Prostate Cancer.

Purpose: Left-digit bias is a phenomenon in which the leftmost digit of a number disproportionately influences decision making. We measured the effect of left-digit age bias on treatment recommendations for localized prostate cancer.

Materials And Methods: We included men with clinically localized prostate adenocarcinoma in Surveillance, Epidemiology, and End Results from 2004 to 2018 and the National Cancer Database from 2004 to 2016.

Trends in Androgen Deprivation Use in Men With Intermediate-Risk Prostate Cancer Who Underwent Radiation Therapy.

Purpose: Until 2018, National Cancer Comprehensive Network guidelines recommended androgen deprivation therapy (ADT) for all men with intermediate-risk prostate cancer who had undergone radiation therapy. Intermediate risk was stratified as favorable and unfavorable in 2018, and ADT recommendation was limited to men with unfavorable intermediate-risk prostate cancer. Data suggesting this stratification and treatment deintensification were first published in December 2013.

Harm-to-Benefit of Three Decades of Prostate Cancer Screening in Black Men.

Background: Prostate-specific antigen screening has profoundly affected the epidemiology of prostate cancer in the United States. Persistent racial disparities in outcomes for Black men warrant re-examination of the harms of screening relative to its cancer-specific mortality benefits in this population.

Methods: We estimated overdiagnoses and overtreatment of prostate cancer for men of all races and for Black men 50 to 84 years of age until 2016, the most recent year with treatment data available, using excess incidence relative to 1986 based on the Surveillance, Epidemiology, and End Results registry and U.

Identification and characterization of TYK2 pseudokinase domain stabilizers that allosterically inhibit TYK2 signaling.

Kinase inhibition continues to be a major focus of pharmaceutical research and discovery due to the central role of these proteins in the regulation of cellular processes. One family of kinases of pharmacological interest, due to its role in activation of immunostimulatory pathways, is the Janus kinase family. Small molecule inhibitors targeting the individual kinase proteins within this family have long been sought-after therapies.